We greatly appreciate the opportunity to submit this Challenge Grant to NIMH under: (15) Translational Science, 15-MH-108, Screening approaches to identify pharmacologic treatments for mental disorders. The objective of this grant is to implement a high throughput screen for small molecules that potentiate the activity of FosB, a transcription factor that promotes resilience and antidepressant-like responses in several animal models and is deficient in the brains of depressed humans. FosB, which is induced in certain brain regions by chronic stress, represents a positive, coping mechanism that promotes positive adaptation to stress. 1) FosB induction in brain by chronic stress correlates with an animal's resilience to the deleterious effects of the stress. 2) Using viral-mediated gene transfer or inducible and brain region-specific bitransgenic mouse models, overexpression of FosB in these specific brain areas is sufficient to render animals resistant to subsequent stress and to reverse behavioral abnormalities induced by chronic stress. 3) Conversely, overexpression of a dominant negative antagonist of FosB in these brain regions makes animals more vulnerable to stress. 4) Chronic administration of standard antidepressant medications also induces FosB in these same brain regions, and overexpression of the dominant negative antagonists of FosB block the antidepressant-like behavioral effects of these medications in several behavioral assays. 5) Depressed humans have lower levels of FosB in these brain regions compared to extensively matched control subjects. This is the ideal time to submit this Challenge Grant, since we are poised to initiate the proposed studies immediately and they can be completed within two years. Thus, Drs. Eric Nestler and Gabby Rudenko have developed a novel high throughput screen to identify small molecule potentiators of FosB. An initial screen of ~50,000 compounds has identified ~500 hits that now require substantial validation. A series of validation assays, first in vitro and then in vivo, have also been developed. While targeting a transcription factor for psychiatric drug development is highly novel, several factors suggest that it represents a viable, albeit high risk, approach. For example, FosB is expressed at low levels throughout brain and peripheral tissues under normal conditions, suggesting considerable tissue specificity. Moreover, even if small molecule FosB activators prove unsuitable for the treatment of depression, high affinity, small molecule ligands for FosB would be invaluable tools to help us better understand FosB action in brain. Such molecules also could potentially be used to image FosB in the living human brain by use of PET or related brain imaging technologies, which would be a major boon to clinical investigations in depression and perhaps represent a novel tool to diagnose depression or other stress-related disorders or to track a patient's progress during treatment. We have recently shown that induction of the transcription factor, DeltaFosB, in brain represents a positive adaptation that helps individuals cope with chronic stress. Interestingly, the protein is also induced in brain by standard antidepressnts treatments, and depressed humans show lower levels of DeltaFosB in brain. We now propose to identify small molecule activators of DeltaFosB as novel treatment agents for depression.